Exposure to dioxin and nonneoplastic mortality in the expanded IARC international cohort study of phenoxy herbicide and chlorophenol production workers and sprayers.

The authors studied noncancer mortality among phenoxyacid herbicide and chlorophenol production workers and sprayers included in an international study comprising 36 cohorts from 12 countries followed from 1939 to 1992. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin or higher chlorinated dioxins (TCDD/HCD) was discerned from job records and company questionnaires with validation by biologic and environmental measures. Standard mortality ratio analyses suggested a moderate healthy worker effect for all circulatory diseases, especially ischemic heart disease, among both those exposed and those not exposed to TCDD/HCD. In Poisson regression analyses, exposure to TCDD/HCD was not associated with increased mortality from cerebrovascular disease. However, an increased risk for circulatory disease, especially ischemic heart disease (rate ratio [RR] 1.67, 95% confidence interval [Cl] 1.23-2.26) and possibly diabetes (RR 2.25, 95% Cl 0.53-9.50), was present among TCDD/HCD-exposed workers. Risks tended to be higher 10 to 19 years after first exposure and for those exposed for a duration of 10 to 19 years. Mortality from suicide was comparable to that for the general population for all workers exposed to herbicides or chlorophenols and was associated with short latency and duration of exposure. More refined investigations of the ischemic heart disease and TCDD/HCD exposure association are warranted.

Elimination of chromium in urine after stainless steel welding.

Nine retired (on an average of four years) stainless steel welders had higher (p less than 0.001) urinary chromium levels [mean 7 (range 3-13) mumol/mol of creatinine] than 21 nonexposed referents [mean less than or equal to 1.5 (range less than 0.6-7) mumol/mol of creatinine] but did not differ in this respect from 14 active welders studied at the end of a 31-d vacation (mean 9, range 4-17). This result shows the existence of a slow compartment for chromium in the body. Urinary chromium on time after the end of exposure was analyzed mathematically by use of an exponential two-compartment model. Good fits were obtained, showing the existence of a fast compartment in addition to the slow one. For four welders followed for 31 d, the biological half-time of the slow compartment ranged from 14 d to infinity. For 12 welders followed for 60 h, the fast compartment had a median half-time of 7 (range 4-35) h. For 19 welders there was a significant (p less than 0.01) correlation between chromium in air (total and soluble hexavalent) and urinary chromium (rs = 0.68 and 0.64). However, the variation of urinary chromium on chromium in air was considerable, especially at chromium air levels at or below the hygienic standards. Correction for urinary chromium levels on Monday morning did not decrease the variation.

Acute respiratory disorder, rhinoconjunctivitis and fever associated with the pyrolysis of polyurethane derived from diphenylmethane diisocyanate.

OBJECTIVES: A case is described of complex reactions associated with exposure to diphenylmethane diisocyanate (MDI), with some immunologic observations. METHODS: Medical history, clinical examinations, and analyses of immunologic parameters and the 4,4'-MDI-related amine 4,4'-diaminodiphenylmethane (MDA) in hydrolyzed serum and urine were used. RESULTS: The patient, a mechanic whose medical history suggested repeated attacks of a work-related pulmonary or systemic disease, was examined because of acute respiratory disorder, rhinoconjunctivitis, and a late systemic reaction after exposure to polyurethane pyrolysis products, including 4,4'-MDI (air level 15 micrograms.m3). Spirometry showed a partly reversible obstructive dysfunction, and a skin-prick test was positive versus isocyanates conjugated with human serum albumin (HSA). MDA was detected in hydrolyzed serum (5.6 ng.ml) and urine (1.6 micrograms.g creatinine-1). In serum, there were specific immunoglobulin (Ig) G (IgG1 and IgG4) and IgE antibodies to 4,4'-MDI-HSA and other isocyanates (phenylisocyanate, toluene diisocyanate, p-toluene monoisocyanate, hexamethylene diisocyanate) conjugated with HSA, a very high total IgE, a raised total IgG, and moderate neutrophilia and eosinophilia. The specific antibodies declined, but were still increased five years later. Furthermore, the values of circulating immune complexes were high. In vitro, the circulating immune complexes in serum increased after the addition of 4,4'-MDI-HSA. The patient had anti-Clq antibodies, which probably accounted for part of the circulating immune complexes. CONCLUSIONS: The reactions associated with MDI exposure (in combination with exposure to pyrolysis products) had features compatible with immediate hypersensitivity and with a complement-mediated immune-complex reaction.

No cytogenetic effects in lymphocytes of stainless steel welders.

In 24 manual metal arc stainless steel welders (means: exposure time 19 years, 100 electrodes/d, air chromium level 81 micrograms/m3, urinary chromium 47 mumol/mol creatinine) and 24 matched referents, lymphocytes in peripheral blood were analyzed for cytogenetic effects. No statistically significant differences were observed as to frequency of cells with breaks and fragments (1.5% for the welders, 1.9% for the referents); gaps and isogaps (1.8 vs 2.0%); interchanges, dicentrics, rings and markers (0.8 vs 0.5%); total number of cells with structural aberrations (4.1 vs 4.4%); hyperdiploidy (0.3 vs 0.2%); or total number of cells with aberrations (4.4 vs 4.6%). Neither were there any differences in the frequencies of micronuclei (7.8 vs 7.9 per mille) or sister chromatid exchanges (11 vs 12 per cell) in lymphocytes of peripheral blood.

4,4'-Methylenedianiline in hydrolysed serum and urine from a worker exposed to thermal degradation products of methylene diphenyl diisocyanate elastomers.

A 45-year-old mechanic employed in blowing hot air (350 degrees-600 degrees C) onto the surface of a polyurethane methylene diphenyl diisocyanate (MDI) conveyer belt developed dyspnoea, rhinoconjunctivitis and fever. The illness was suggestive of an MDI-associated illness, compatible with both immediate hypersensitivity and a complement-mediated immune-complex reaction. In his serum there were specific IgG and IgE antibodies against MDI and other isocyanates, and high values of circulating immune complexes. The patient's blood and urine samples were analysed for the presence of 4,4'-methylenedianiline (MDA) in hydrolysed urine and plasma. MDA was derivatized to amides using pentafluoropropionic acid anhydride (PFPA). Gas chromatography-mass spectrometry determinations were made monitoring the (M-20; M = molecular mass) fragments from the MDA-PFPA and the [2H2]MDA-PFPA derivative. The first urine sample was obtained 22 h and the last sample 114 h after start of exposure. The urine concentrations of MDA were corrected for creatinine. The half-time of MDA was 70-80 h. The first serum sample was obtained 19 h and the last sample 1967 days after the start of exposure. The half-time was 21 days, which suggests the presence of MDI/MDA plasma protein adducts in the exposed worker.

Kidney function in stainless steel welders.

Seventeen male manual metal-arc stainless steel welders (mean exposure time 20 years) had far higher levels of chromium in urine than individually matched controls (medians 23 vs 1.5 mumol/mol creatinine; 10.5 vs 0.7 microgram/g creatinine). However, there were no signs of kidney damage in tests of function of tubuli (beta-hexosaminidase, lysozyme, and beta 2-microglobuline) or glomeruli (albumine clearance).

Mortality and tumour morbidity among Swedish market gardeners and orchardists.

In order to investigate possible effects of exposure to pesticides, mainly fungicides and insecticides, we studied a cohort of 2370 subjects, who, during the period 1965-1982, had been members of a horticulturists' trade association (market gardeners and orchardists). Compared to a regional reference population, total mortality (542 deaths; standardized mortality morbidity ratio, SMR = 0.8; 95% confidence limits, CLs = 0.7, 0.9) and mortality due to malignant tumours (133 deaths, SMR = 0.9; CLs = 0.7, 1.0), and cardiovascular and respiratory deaths were somewhat decreased. Suggestive excesses in mortality were seen for mental disorders and tumours of the stomach, skin and nervous system. The tumours of the nervous system were in particular excess in the young and middle-aged horticulturists (below age 60; six cases, SMR = 2.9; CLs = 1.1, 6.2). During the period 1965-1986, the total tumour morbidity was slightly decreased (255 cases; SMR = 0.9; CLs = 0.8, 1.0), as were gastrointestinal and respiratory tract tumours. The incidence of melanomas was increased (15 cases, SMR = 2.1; CLs = 1.2, 3.5), and tumours of the female genital organs, myelomas, and brain tumours (12 cases, SMR = 1.5; CLs = 0.8, 2.7) were slightly numerically elevated. Brain tumours in the young and middle-aged horticulturists (11 cases, SMR = 3.2; CLs = 1.6, 5.7), including meningiomas (four observed, SMR = 6.8; CLs = 1.9, 17.4), were increased, especially in the period 1975-1979. The mortality and tumour morbidity patterns in gardeners and orchardists, analysed separately, were similar to the patterns in all the horticulturists.(ABSTRACT TRUNCATED AT 250 WORDS)

Focal epilepsy and exposure to organic solvents: a case-referent study.

Organic solvent exposure was studied in 104 cases of idiopathic focal epilepsy and 312 matched referents. Exposure to solvents was classified as O, I, II, or III on the basis of occupational codes. The relative risk (RR) of epilepsy for those in exposure class I, II, or III, relative to O, was estimated using conditional logistic regression. An increasing trend in RR was observed with higher exposure classes. The attributable risk for cases with focal epilepsy of deep hemispherical origin was estimated to be 8%.

Exposure biomarkers and risk from gluing and heating of polyurethane: a cross sectional study of respiratory symptoms.

OBJECTIVES: To define the relation between exposure to polyurethane (PUR) glue, biomarkers of exposure and effect, and work related symptoms that occur at least once a week. METHODS: In a cross sectional study, 152 workers and 14 clerks in a factory with exposure to sprayed and heated PUR glue containing 4, 4'-diphenylmethane (MDI) or 1,6-hexamethylene (HDI) di-isocyanate were examined with gas chromatography-mass spectrometry (GC-MS) for metabolites of MDI in plasma (P-MDX) and urine (U-MDX), 2,4- and 2, 6-toluene di-isocyanate (TDI; P-TDX, U-TDX) and HDI in plasma and urine, specific serum IgG (S-IgG-MDI, S-IgG-HDI, and S-IgG-TDI, respectively) and IgE (S-IgE-MDI). Work related symptoms of the eyes and airways (nose or lower airways, or both), and lung function were also evaluated. RESULTS: P-MDX was detected in 65% of the workers, U-TDX in 47%, HDX in none. Three per cent were positive for S-IgE-MDI, 33% for S-IgG-MDI, 32% for S-IgG-TDI, and 12% for S-IgG-HDI. A few clerks had metabolites, and some had antibodies. Most metabolites and immunoglobulins were slightly correlated-for example, P-MDX v S-IgG-MDI: r(s)=0.21. Workers who heated glue had increased P-MDX (odds ratio (OR)=12 for a value above the median) and S-IgG-MDI (OR=3.7), sprayers P-2,4-TDX (OR=6.2) and P-2,6-TDX (OR=16). Twenty six per cent of the workers had work related symptoms of the airways, 21% from the nose, 11% from the lower airways. Spraying of glue increased the risk of work related symptoms and slightly decreased lung function. U-MDX was associated with work related symptoms from the airways (OR=3.7) and P-2,6-TDX with work related symptoms from the lower airways (OR=6.6). S-IgG-MDI was related to work related symptoms from the airways (OR=2.6). CONCLUSIONS: There were relations between exposures to sprayed and heated PUR glue based on MDI and HDI, concentrations of metabolites of MDI and TDI in plasma and urine, specific IgG serum antibodies against MDI, TDI, and HDI, and work related symptoms.

Biomarkers of exposure, antibodies, and respiratory symptoms in workers heating polyurethane glue.

OBJECTIVES: The pathogenic basis of respiratory disorders associated with isocyanates are still obscure. One reason for this is the lack of good estimates of human exposure. In this study exposure was estimated by measurement of isocyanate metabolites in biological samples. METHODS: In a factory using isocyanate based polyurethane (PUR) glue, isocyanate concentrations in air were measured by liquid chromatography. Samples from 174 employees were analysed for metabolites of 4,4'-methylene diphenyl diisocyanate (MDI) in plasma (P-MDX) and urine (U-MDX). After hydrolysis, 4,4'-methylenedianiline was measured by gas chromatography-mass spectrometry (GC-MS). The employees were screened for work related respiratory symptoms and tested for specific immunoglobulin E (IgE) and IgG antibodies directed against isocyanate conjugated to human serum albumin. RESULTS: The time weighted isocyanate concentrations in air were low (MDI < 0.2-7; hexamethylene diisocyanate (HDI) < 0.1-0.7; 2,6-toluene diisocyanate (TDI) < 0.1 microgram/m3). All subjects had detectable P-MDX and U-MDX. There were significant associations between the estimates of exposure to thermal degradation products of an MDI based glue and P-MDX (range < or = 0.10-5.5 micrograms/l); and U-MDX (< or = 0.04-5.0 micrograms/g creatinine); in cases of heavy exposure. P-MDX and U-MDX were associated with each other (r = 0.64; P = 0.0001), work related symptoms (P-MDX: P = 0.03; Mann-Whitney U test), and serum concentrations of MDI specific IgG antibodies (r = 0.26; P = 0.0007). Unexpectedly, high P-MDX and U-MDX concentrations were also encountered in workers cutting textile (P-MDX 2.4-4.5 micrograms/l; U-MDX 0.81-3.8 micrograms/g creatinine); the reason is still unknown. Equally unexpected, there were significant negative associations between P-MDX and liver function tests. CONCLUSIONS: The results clearly show the value of biomarkers for isocyanate exposure; in particular, P-MDX is useful. Further, these results show the risk connected with thermal degradation of PUR.

Cancer incidence and mortality in women occupationally exposed to chlorophenoxy herbicides, chlorophenols, and dioxins.

The association between exposure to chlorophenoxy herbicides contaminated with dioxins and occurrence of cancer has been studied mainly in male populations. In animal experiments, gender differences have been recorded in the cancer response to administered 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Mortality and cancer incidence in an international cohort of 701 women from an International Register of Workers occupationally exposed to chlorophenoxy herbicides, chlorophenols, and dioxins is examined. Cause-specific, national death rates and cancer incidence rates were used as referents. Cancer risk was not increased overall, with a standardized incidence ratio (SIR) of 96 and 95 percent confidence interval (CI) of 64-137, based on 29 cases. Among workers exposed to those chlorophenoxy herbicides contaminated with TCDD, excess cancer incidence (for all sites) was observed (SIR = 222, CI = 102-422, 9 cases); this was highest in the first 10 years after exposure. No excess was observed for breast cancer, the most common cancer in this cohort. Results on cancer mortality were consistent with those on incidence.

Chemical exposure in manufacture of phenoxy herbicides and chlorophenols and in spraying of phenoxy herbicides.

Exposure patterns are reported for manufacturing and sprayer cohorts incorporated in the "IARC International Register of Workers exposed to Phenoxy Herbicides and Contaminants." Information was based on company questionnaires, company reports, plant visits, and serum 2, 3, 7, 8-TCDD measurements. In addition to phenoxy herbicides and chlorophenols, workers in manufacturing plants may have been exposed to raw materials, process chemicals, other agents synthesized or formulated, and impurities of all these agents. Sprayers also had a complex exposure pattern, including phenoxy herbicides and some other pesticides, their carriers and additives, and residues of chemicals formed during manufacture. Occurrence of agents, including dioxins, varied between countries. Biological monitoring and industrial hygiene data were rarely available, most since the late 1970s. Exposure of workers depended mainly on the jobs they performed, but several factors influenced level of exposure. A quantitative exposure classification is not feasible in this study. Semiquantitative exposure estimates may be derived through a critical interpretation of biological monitoring and industrial hygiene data together with individual work histories.

Soft tissue sarcoma and non-Hodgkin's lymphoma in workers exposed to phenoxy herbicides, chlorophenols, and dioxins: two nested case-control studies.

We examined the effect of exposure to chemicals present in the production and spraying of phenoxy herbicides or chlorophenols in two nested case-control studies of soft tissue sarcoma and non-Hodgkin's lymphoma. Eleven sarcoma and 32 lymphoma cases occurring within an international cohort were matched for age, sex, and country of residence with 55 and 158 controls, respectively. Exposures to 21 chemicals or mixtures were estimated by three industrial hygienists who were blind to the subject's case-control status. Excess risk of soft tissue sarcoma was associated with exposure to any phenoxy herbicide [odds ratio (OR) = 10.3; 95% confidence interval (CI) = 1.2-91] and to each of the three major classes of phenoxy herbicides (2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid, and 4-chloro-2-methylphenoxyacetic acid), to any polychlorinated dibenzodioxin or furan (OR = 5.6; 95% CI = 1.1-28), and to 2,3,7,8-tetrachlorodibenzo-p-dioxin (OR = 5.2; 95% CI = 0.85-32). Sarcoma risk was not associated with exposure to raw materials or other process chemicals. In the non-Hodgkin's lymphoma study, associations were generally weaker than those found in the study on sarcoma. These findings indicate that workers exposed to phenoxy herbicides and their contaminants are at a higher risk of soft tissue sarcoma.

Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols.

Epidemiological studies have revealed an increased risk of cancer, notably soft-tissue sarcomas and non-Hodgkin's lymphomas, in people occupationally exposed to chlorophenoxy herbicides, including those contaminated by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD). We report here a historical cohort study of mortality in an international register of 18,910 production workers or sprayers from ten countries. Exposure was reconstructed through questionnaires, factory or spraying records, and job histories. Cause-specific national death rates were used as reference. No excess was observed in all-cause mortality, for all neoplasms, for the most common epithelial cancers, or for lymphomas. A statistically non-significant two-fold excess risk, based on 4 observed deaths, was noted for soft-tissue sarcoma with a standardised mortality ratio (SMR) of 196 and 95% confidence interval (Cl) 53-502; this was concentrated as a six-fold statistically significant excess, occurring 10-19 years from first exposure in the cohort as a whole (SMR = 606 [165-1552]) and, for the same time period, as a nine-fold excess among sprayers (SMR = 882 [182-2579]). Risks appeared to be increased for cancers of the testicle, thyroid, other endocrine glands, and nose and nasal cavity, based on small numbers of deaths. The excess of soft-tissue sarcomas among sprayers is compatible with a causal role of chlorophenoxy herbicides but the excess does not seem to be specifically associated with those herbicides probably contaminated by TCDD.

Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins. An expanded and updated international cohort study.

The authors examined cancer mortality in a historical cohort study of 21,863 male and female workers in 36 cohorts exposed to phenoxy herbicides, chlorophenols, and dioxins in 12 countries. Subjects in this updated and expanded multinational study coordinated by the International Agency for Research on Cancer were followed from 1939 to 1992. Exposure was reconstructed using job records, company exposure questionnaires, and serum and adipose tissue dioxin levels. Among workers exposed to phenoxy herbicides contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or higher chlorinated dioxins, mortality from soft-tissue sarcoma (6 deaths; standardized mortality ratio (SMR) = 2.03, 95% confidence interval (CI) 0.75-4.43) was higher than expected from national mortality rates. Mortality from all malignant neoplasms (710 deaths; SMR = 1.12, 95% CI 1.04-1.21), non-Hodgkin's lymphoma (24 deaths; SMR = 1.39, 95% CI 0.89-2.06), and lung cancer (225 deaths; SMR = 1.12, 95% CI 0.98-1.28) was slightly elevated. Risks for all neoplasms, for sarcomas, and for lymphomas increased with time since first exposure. In workers exposed to phenoxy herbicides with minimal or no contamination by TCDD and higher chlorinated dioxins, mortality from all neoplasms (398 deaths; SMR = 0.96, 95% CI 0.87-1.06), non-Hodgkin's lymphoma (9 deaths; SMR = 1.00), and lung cancer (148 deaths; SMR = 1.03) was similar to that expected, and mortality from soft-tissue sarcoma was slightly elevated (2 deaths; SMR = 1.35). In a Poisson regression analysis, workers exposed to TCDD or higher chlorinated dioxins had an increased risk for all neoplasms (rate ratio = 1.29, 95% CI 0.94-1.76) compared with workers from the same cohort exposed to phenoxy herbicides and chlorophenols but with minimal or no exposure to TCDD and higher chlorinated dioxins. These findings indicate that exposure to herbicides contaminated with TCDD and higher chlorinated dioxins may be associated with a small increase in overall cancer risk and in risk for specific cancers.